The mechanisms of binding and entry of varicella-zoster virus (VZV) are not understood. These early events in the life cycle of the VZV virus are important to our understanding and our attempts to control diseases caused by this herpesvirus. VZV is unique among human alpha-herpesviruses in that it lacks glycoprotein D, the glycoprotein reported to interact with the known herpesvirus coreceptors. We are investigating the binding of VZV glycoproteins to cell membranes, to isolated proteins, and to glycosaminoglycans. We have cloned the genes for the major envelope glycoproteins of VZV into high level expression vectors including the baculovirus expression system. Secreted soluble forms of the VZV glycoprotein B, glycoprotein C, glycoprotein E, and glycoprotein I were expressed and purified in large amounts to allow for biochemical, immunological, and functional studies of these proteins. The ability of these glycoproteins to inhibit VZV infections in vitro by binding to cell-surface receptors is being examined. Monoclonal antibodies to cell membrane proteins are being developed to identify specific cell surface membrane proteins that serve as receptors for VZV envelope glycoproteins. The ability of the immune response to these glycoproteins to prevent VZV disease in a small animal model system is being investigated.